In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. The central aim is to identify approaches that will result in a net therapeutic gain, thus improving cancer treatment with radiation. One goal of the project is to define and better understand those aspects of tumor physiology, including cellular and molecular processes and the influence of the tumor microenvironment on treatment response. The ability to enhance the response of the tumor to radiation, without enhancing normal tissue within a given treatment field is desirable. We have completed and published a study evaluating a PI3K/mTOR inhibitor in human head/neck carcinoma cells lines. Impressive radiosensitization by the inhibitor is observed in vitro and in vivo. No toxicity of the combination was observed in vivo. The mechanism of action of the inhibitor was found to be inhibition of radiation-induced DNA damage repair. The results of this pre-clinical study will provide the necessary information to consider a clinical human trial with this agent as a radiation sensitizer. We have demonstrated that a novel HSP90 inhibitor is a radiation sensitizer (in vitro and in vivo). Significant in vitro radiation dose modification factors have been observed with this agent and xenograft studies are ongoing. This agent also has potential of being translated into human clinical trials. We have initiated preliminary in vitro studies evaluating a CDK4/6 inhibitor, which demonstrates significant radiosensitization. We continue to evaluate a number of metabolic inhibitors as radiation modifiers under the working hypothesis that inhibition of metabolism (for example, decreased ATP production) will diminish the repair of radiation-induced DNA damage. We are currently evaluating a novel lactate dehydrogenase inhibitor with and without a glutamine inhibitor as potential radiation modifiers of cancer cell growth. With respect to normal tissue response to radiation, we completed a study demonstrating that rapamycin supplied in the animal's chow protects against radiation-induced lung fibrosis in part by preventing radiation induced stem cell senescence. We continue to develop an test novel functional imaging platforms to better understand the contribution of tumor hypoxia and metabolism on radiation and drug induced tumor response in tumor-bearing animals. Collectively we have identified a number of pre-clinical approaches to initiate human radiation oncology clinical trials for modulation of radiation effects on tumors and normal tissues.